Roles of RIPK1 as a stress sentinel coordinating cell survival and immunogenic cell death

Clucas, Jarama; Meier, Pascal

doi:10.1038/s41580-023-00623-w

Cited by 16 publications

(14 citation statements)

References 208 publications

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“…RIPK1 is a multi-functional protein and central regulator of cell death, inflammatory processes, and immune responses (Figure 3A) . Generally, RIPK1 can promote both, cell survival as well as cell death, highly depending on the regulatory inputs received from the cellular environment (Degterev et al (2019), Clucas and Meier (2023), Silke and Meier (2013)) . Genetic alterations of RIPK1 are linked to immune and autoinflammatory diseases.…”

Section: Resultsmentioning

confidence: 99%

“…RIPK1 acts as a central stress sensor to control cell survival, inflammation and cell death signaling (Clucas and Meier (2023)) . Deregulation of RIPK1 and RIPK3-involved signaling cascades have been linked to inflammatory bowel diseases, rheumatoid arthritis, autoimmune conditions and neuroinflammatory diseases such as Alzheimer’s and Parkinson’s disease (Martens et al (2020), Li et al (2019), Speir et al (2021), Clucas and Meier (2023)) . This is believed to be related to deregulations of both catalytic and scaffolding functions.…”

Section: Introductionmentioning

confidence: 99%

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Kinases in motion: impact of protein and small molecule interactions on kinase conformations

Kugler,

Schwaighofer,

Feichtner

et al. 2024

Preprint

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Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the Kinase Conformation (KinCon)-reporter system. We first tracked BRAF-kinase activity conformation changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1-kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP-kinases in response to TNF-pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps identify cellular factors that impact drug efficacies. The understanding of the dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kinases in motion: impact of protein and small molecule interactions on kinase conformations

Kugler,

Schwaighofer,

Feichtner

et al. 2024

Preprint

Self Cite

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“…IKKβ in the complex is then phosphorylated and activated by TAK1, leading to the phosphorylation, ubiquitination, and degradation of IκB. NF-κB subsequently translocates into the nucleus to activate gene expression 45 , 46 . TIGAR can interact with HK2, AKT, NRF2, and so on in different cells 15 – 18 , 23 .…”

Section: Discussionmentioning

confidence: 99%

Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis

Wang,

Li,

Yang

et al. 2024

Nat Commun

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Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.

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“…RIPK1, for example, was first identified by virtue of death domain interactions with the cell surface receptor CD95 and was therefore referred to as “receptor interacting protein”. RIPK1 and RIPK3 are directly relevant to septic immune dysfunction, as each play a central role in mediating cell inflammation as well as death by necroptosis ( 23 ).…”

Section: Key Pcd Componentsmentioning

confidence: 99%